Femtowatt non-vacuum tube detector assembly

ABSTRACT

In one embodiment, a femtowatt sensitivity optical detector is provided using one or more photodiodes, intended as a replacement for the photomultiplier based photon counting unit.

BACKGROUND

Photomultiplier tubes (PMTs for short), members of the class of vacuumtubes, and more specifically vacuum phototubes, are extremely sensitivedetectors of light in the ultraviolet, visible, and near-infrared rangesof the electromagnetic spectrum. Unfortunately, current techniques ofmanufacturing PMTs is a tedious and costly process. Many manufacturershave opted to stop production of PMTs due these challenges. In additionto manufacturing issues, although highly sensitive, PMTs also saturateeasily when too much light reaches it.

SUMMARY

At least some of the disadvantages associated with the prior art areovercome by at least some embodiments of the devices and methodsdescribed herein.

In one embodiment, a femtowatt sensitivity optical detector is providedusing one or more photodiodes, intended as a replacement for thephotomultiplier based photon counting unit.

In one embodiment, the system is comprised of four main components:Multiple photodiodes, which act as optical transducers by producing anelectrical signal in the form of a current proportional to the detectedoptical power (number of photons). 1) Analog amplification system,composed of a high gain transimpedance amplifier (TIA) and buffer oneach photodiode, followed by a fully differential amplifier to combinethe outputs of the multiple TIAs. 2) Digital acquisition system,composed of an analog to digital converter (ADC), followed by anprogrammable processor, which is linked to the central processor as wellas on board memory. The programmable processor implements the dataacquisition algorithm such as an average or other algorithm. 3) Multipledigital to analog converters (DACs) on the programmable processor areused to provide feedback control—one for offset adjustment in thedifferential amplifier, and one to the set the reference level of theADC. 4) Mechanical housing module, in which the electronics iscontained.

This Summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This Summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended tobe used to limit the scope of the claimed subject matter.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.However, in the event of a conflict between the content of the presentexpress disclosure and the content of a document incorporated byreference herein, the content of the present express disclosurecontrols.

COPYRIGHT

This document contains material subject to copyright protection. Thecopyright owner (Applicant herein) has no objection to facsimilereproduction of the patent documents and disclosures, as they appear inthe US Patent and Trademark Office patent file or records, but otherwisereserves all copyright rights whatsoever. The following notice shallapply: Copyright 2013-14 Theranos, Inc.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 3 show schematics of systems according to embodimentsdescribed herein.

FIGS. 4 to 5 show schematics of systems according to embodimentsdescribed herein.

FIG. 6 shows a side view of one assembly herein using a reflectoraccording to at least one embodiment described herein.

FIG. 7 shows a perspective view of one assembly herein using a reflectoraccording to at least one embodiment described herein.

FIG. 8 show a schematic of an assembly according to embodimentsdescribed herein.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed. It may be notedthat, as used in the specification and the appended claims, the singularforms “a”, “an” and “the” include plural referents unless the contextclearly dictates otherwise. Thus, for example, reference to “a material”may include mixtures of materials, reference to “a compound” may includemultiple compounds, and the like. References cited herein are herebyincorporated by reference in their entirety, except to the extent thatthey conflict with teachings explicitly set forth in this specification.

In this specification and in the claims which follow, reference will bemade to a number of terms which shall be defined to have the followingmeanings:

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.For example, if a device optionally contains a feature for a samplecollection unit, this means that the sample collection unit may or maynot be present, and, thus, the description includes both structureswherein a device possesses the sample collection unit and structureswherein sample collection unit is not present.

As used herein, the terms “substantial” means more than a minimal orinsignificant amount; and “substantially” means more than a minimally orinsignificantly. Thus, for example, the phrase “substantiallydifferent”, as used herein, denotes a sufficiently high degree ofdifference between two numeric values such that one of skill in the artwould consider the difference between the two values to be ofstatistical significance within the context of the characteristicmeasured by said values. Thus, the difference between two values thatare substantially different from each other is typically greater thanabout 10%, and may be greater than about 20%, preferably greater thanabout 30%, preferably greater than about 40%, preferably greater thanabout 50% as a function of the reference value or comparator value.

As used herein, a “sample” may be but is not limited to a blood sample,or a portion of a blood sample, may be of any suitable size or volume,and is preferably of small size or volume. In some embodiments of theassays and methods disclosed herein, measurements may be made using asmall volume blood sample, or no more than a small volume portion of ablood sample, where a small volume comprises no more than about 5 mL; orcomprises no more than about 3 mL; or comprises no more than about 2 mL;or comprises no more than about 1 mL; or comprises no more than about500 μL; or comprises no more than about 250 μL; or comprises no morethan about 100 μL; or comprises no more than about 75 μL; or comprisesno more than about 50 μL; or comprises no more than about 35 μL; orcomprises no more than about 25 μL; or comprises no more than about 20μL; or comprises no more than about 15 μL; or comprises no more thanabout 10 μL; or comprises no more than about 8 μL; or comprises no morethan about 6 μL; or comprises no more than about 5 μL; or comprises nomore than about 4 μL; or comprises no more than about 3 μL; or comprisesno more than about 2 μL; or comprises no more than about 1 μL; orcomprises no more than about 0.8 μL; or comprises no more than about 0.5μL; or comprises no more than about 0.3 μL; or comprises no more thanabout 0.2 μL; or comprises no more than about 0.1 μL; or comprises nomore than about 0.05 μL; or comprises no more than about 0.01 μL.

As used herein, the term “point of service location” may includelocations where a subject may receive a service (e.g. testing,monitoring, treatment, diagnosis, guidance, sample collection, IDverification, medical services, non-medical services, etc.), and mayinclude, without limitation, a subject's home, a subject's business, thelocation of a healthcare provider (e.g., doctor), hospitals, emergencyrooms, operating rooms, clinics, health care professionals' offices,laboratories, retailers [e.g. pharmacies (e.g., retail pharmacy,clinical pharmacy, hospital pharmacy), drugstores, supermarkets,grocers, etc.], transportation vehicles (e.g. car, boat, truck, bus,airplane, motorcycle, ambulance, mobile unit, fire engine/truck,emergency vehicle, law enforcement vehicle, police car, or other vehicleconfigured to transport a subject from one point to another, etc.),traveling medical care units, mobile units, schools, day-care centers,security screening locations, combat locations, health assisted livingresidences, government offices, office buildings, tents, bodily fluidsample acquisition sites (e.g. blood collection centers), sites at ornear an entrance to a location that a subject may wish to access, siteson or near a device that a subject may wish to access (e.g., thelocation of a computer if the subject wishes to access the computer), alocation where a sample processing device receives a sample, or anyother point of service location described elsewhere herein.

Referring now to FIG. 1, one non-limiting example of photodiode (PD)placement is shown, relative to the chemiluminescent sample 10. Thearrows 20 indicate the direction of emitted of photons. In onenon-limiting example, the photodiodes 30 and 40 are operated in zerobias mode—this ensures that the only source of noise is thermal noise.They are situated as close as possible to the chemiluminescent sample,allowing the collection of as much emitted light as possible. Inaddition, pairs of photodiodes are on equal and opposite sides of thesample, ensuring a symmetric collection of light. FIG. 1 illustrates theplacement of two photodiodes, and the design is readily extended tomultiple photodiodes.

In one non-limiting example, the output of each photodiode is a currentproportional to the amount of light incident. For a sample whoseemission is constant in time, this generates a DC current. By way ofexample and not limitation, silicon photodiodes with the followingproperties are used for the photodiodes 30 and 40: Large active area,Low noise equivalent power, High sensitivity (in % quantum efficiency orresponsivity A/W).

Analog Amplification System

Referring now to FIG. 2, an analog amplification system suitable to becoupled to the photodiodes 30 and/40 will now be described. By way ofexample and not limitation, an analog amplifier system in thisembodiment is comprised of three stages as shown in FIG. 2. The dottedlines suggest the possible extension of the amplifier to includemultiple photodiodes.

In this non-limiting example, one stage is a high gain transimpedanceamplifier (TIA), with gain of 10¹⁰ V/A or greater. Each photodiode inthe system is connected to a TIA, whose input is the DC signal currentfrom the photodiode. The output of the TIA is a DC voltage.

In this non-limiting example, one stage is a buffer stage following thetransimpedance amplifier, to isolate the first stage from later stages.

In this non-limiting example, one stage is a differential amplifier (DA)stage, which combines the outputs from multiple transimpedanceamplifiers. The differential amplifier is comprised of a positive andnegative output, such that (V_(out) ⁺−V_(out) ⁻)=A (V_(in) ⁺−V_(in) ⁻),where A is the gain. This gain is adjustable and controlled by thedigital acquisition system, so as to maximize the output range for theparticular sample under test.

The analog amplification system for a pair of photodiodes is illustratedin FIG. 2. Single or multiple pairs of photodiodes are connected inopposite directions. Thus, the optical signal component of V_(out) ⁻ isalways 180 degrees out of phase with that of V_(out) ⁺, resulting in upto twice the signal when the difference (V_(out) ⁺−V_(out) ⁻) ismeasured for two photodiodes. All other common signals (60 Hz pickup, DCdrift, etc) are in phase along the different paths, and therefore cancelout when the difference is measured. Noise adds in quadrature, giving1.4 times the noise on each path, in the case of two photodiodes.

Furthermore, each stage of the analog amplifier may optionally contain alow pass filter for additional noise reduction.

Digital Acquisition System

Referring now to the embodiment of FIG. 3, one non-limiting example of acomplete photodiode detector system will now be described. The schematicof FIG. 3 shows the components and connections between the analog anddigital system. The digital acquisition system, in relation to theanalog system is illustrated in FIG. 3. In this non-limiting example,the outputs of the analog amplifier system (V_(out) ⁺ and V_(out) ⁻) arefed into the digital acquisition system, comprised of:

A differential analog-to-digital converter (ADC), with high samplingrate (>1 MSPS) and high precision (>16 bits). The output of the ADC is adigital signal representing the difference (V_(out) ⁺−V_(out) ⁻).

An digital processor, which collects the data from the ADC over a settime interval, and implements an algorithm whose output is digitallyprocessed. By way of non-limiting example, the sample may be processedby performing one or more the following digital signal processing on thedata collected: smoothing data processing, additive smoothing,Savitzky-Golay smoothing, moving average smoothing, local regressionsmoothing, Butterworth filtering, Kalman filtering, Kernel smoothing,Laplacian smoothing, Stretched grid method smoothing, low-passfiltering, recursive filter median, long time average, any single ormultiple combination of the foregoing, or other digital processingtechniques to remove noise. This latter process measures the DC level ofthe signal of interest, and further reduces the noise level. A digitalprocessor such as that available from ARM, Texas Instruments, or thelike can configured for use herein.

The digital processor may also contain digital-to-analog converters(DAC), one of which is used to compensate any DC level offset of the DAoutput (due to natural processes such as amplifier drift and leakagecurrents). A second DAC is used to adjust the range of the ADC. The ARMalso controls the gain of the DA stage. These three feedback controlsmaximize the dynamic range and measurement precision for a particularsample being tested.

Finally, the digital processor optionally converts the measured DCsignal to an equivalent photon count.

Mechanical Housing Module

The mechanical housing in which the above electronics are contained isdesigned with the following requirements:

Multiple circuits (and sub-circuits) are isolated from each other bygrounded surfaces, to prevent parasitic capacitive and inductivecross-talk.

The complete system is isolated from the environment, by ensuring thatthe housing is made of a grounded, conductive material (e.g. aluminum).This minimizes pickup from the environment, such as 60 Hz and otherelectromagnetic interference.

Control System

One embodiment of the analog capture system in FIG. 2 that collectsignal from the photodiodes has a differential amplifier mode. In thisnon-limiting example, there is a front-end photodiode circuit whichprovides an analog front end. To detect photons at low light levels (say1000 photons per second) versus regular light (billons of photons). Thesignal is very small that is then amplified to be above the noise level.A PMT has an in-built gain system that allows it amplify signal withoutnoise. It is a single photon counter, but it is hard to manufacture andsaturates easily.

In one embodiment, a femtowatt level sensitivity optical detector isprovided using at least one photodiode. It can be configured to providePMT-level sensitivity. In one embodiment, at least two photodiodedetectors are used to detect signal from the sample as seen in FIG. 1. Acontrol circuit is used to combine the signal in a differential manner.One manner is to add the signals to get a total signal out. The otherway is to use a differential mode where one signal is a positive signaland the other is a negative signal and then instead of adding, they areput through a subtraction to substrate the negative signal. Becausenoise does not care if it is positive or negative, the presentembodiment can use a subtraction function when signals are combined tominus out the noise (whereas using addition would not). The ability tohave two, four, six, or other number of combination can be combined atthe control. Many photodiodes can be added the embodiment of FIG. 1 andbe supported by analog systems of FIG. 2 for signal capture. This cancollect more light than the PMT and in theory can go to more sensitivechemistries since more light is being collected.

Embodiments herein can also correlate its output (in volts) to that ofthe with PMT sample device (output in photon counts). Photodiode detects10 times more light, but it can be configured to correlate to PMT typeoutput.

It should be understood that a PMT will saturate at 500000 photons perhalf second. (200 to 200k) The photodiode can measure 2 million per halfsecond. This provides much more tolerance for situations.

As seen in FIG. 4, one embodiment of the system uses a plurality of highgain photodiodes to collect light from multiple locations around thesample and then direct the detected signal to the control board that hasan analog front end similar to that in FIG. 2 to prepare the analogsignal which is then processed digitally in the digital portion shown inFIG. 3. Some embodiment can envision a sphere or other configuration ofmany multiple photodiodes position to capture light from the sample inmany directions.

As seen in FIG. 4, one embodiment of the control board can combinephotodiode signals as a sum, or differentially. In both cases, the noiseadds in quadrature, e.g. if two photodiodes are used, with noises N₁ andN₂, then total noise is:

N=√{square root over (N ₁ ² +N ₂ ²)}

Signals on the other hand, add linearly; so the total signal is S₁+S₂ inthe case of two photodiodes. Thus signal to noise always improves.Differential mode allows removal of common unwanted signals; some mayhave the photodiodes have alternating polarity (cathode grounded, anodegrounded).

Reflector System

It should be understood that electronics generally adds noise. Thusadding even more photodiodes, while increase light capture, can alsodetrimentally increase noise levels. One option is to minimizeelectronics but increase the amount of light collected at any onesensor. One option is to move photodiode closer to sample. Some maycombine both of the foregoing.

As seen in FIG. 5, a still further embodiment of a non-vacuum tubefemotwatt detector will now be described. In this embodiment, thereflector is custom designed to increase light capture. Some embodimentsmay have one or more opening is there for the sample tip to be loweredinto the area of the reflector. Some light will pass through the sample(and it does not excite the sample). This could be an asphericalreflector. Reflection can be aluminum or other reflective material forall wavelength reflection without absorbance.

FIG. 5 shows that this embodiment captures light that would otherwisenot reach the high gain photodiode and redirects it toward the one ormore photodiodes. Some embodiments may use a hemispherical reflector, adish-shaped detector, a curved detector, or the like. Optional lens 116may be positioned to collect emitted and reflected light.

It should be understood that irradiance is smaller if power is spreadoutover a larger area. There may be some benefit to lens 116 to focus lightto exceed a minimum turn-on threshold or reach a threshold irradiancefor certain types of sensors. Optionally, for a CCD sensor, light isspread over too many pixels. Then if it does not overcome light perpixel, it may help for turn-on. CCD type application may be useful fordetermining how much light is coming from each location in the sample.In one embodiment, this turns this system into an imaging device throughthe use of CCDs.

FIG. 6 shows the wall surfaces 100 that are around the photodiode butperhaps not part of the reflector 110 may also be configured to bereflective. FIG. 6 also shows that for various reasons, some embodimentmay have a transparent cover 120 over the photodiode. In one embodiment,the transparent cover 120 is electrically insulating. In one embodiment,the transparent cover 120 is electrically conductive. Optionally, onecould switch off the photodiode while the sample is moving intoposition. Once the sample is in place, then the photodiode switches onto measure. This has the added advantage that since we are essentiallyresetting the device during every read, the electronics is not allowedto drift over time or be affected by parasitic light sources. Althoughonly one photodiode is shown in FIGS. 5 and 6, it should be understoodthat could place multiple photodiodes to maximize collection efficiency

FIG. 7 shows a perspective view of one embodiment of the system with areflector 110. FIG. 7 shows that in this non-limiting example, there maybe an opening 112 that allows for a sample to be lowered into positionfor analysis. A second opening 114 can also be positioned there to allowfor sample fluid to drip out and not collect inside the reflector 110.Optionally, there can be lid that covers the opening 112 and/or 114 toincrease the amount of light capture. There can also be embodimentswhere the entire reflector 110 comes away to allow for sample loading.Optionally, a holder can be mounted in the reflector 110 so that thesample handling system is not holding the sample 10 during detection.

Dual Fluoro-Luminometer

Referring now to FIG. 8, it should be understood that some embodimentsmay combine the system to have both fluorometer and a luminometerfunctions. By way of non-limiting example, an LED or laser can be usedto excite the sample. Some embodiments add a light excitation source andthus does not use a reflector. Optical barrier 130 is used to reducebleed-through. By way of example and not limitation, a cube shapedvessel 140 may be used to reduce scatter/bleed through, or a tip vesselwith a truncated cone shape.

It should be understood that one could have more than one control boardto read more than one device. The control board above in FIG. 8 that hasfeature set forth in FIGS. 2 and 3 is designed to have the ability toread multiple photodiodes in different modes. When run simultaneously,the control board can combine signals from different photodiodes. Thiscan be done in summing or differential mode as described above. When runindividually, the control board can read signals from selectedphotodiodes. Optionally, in a combination of these two cases, where wecan selectively read some of the photodiodes and combine theirsignals—e.g. one can read 3 out of 4 photodiodes simultaneously, andignore the 4th. This flexibility allows the system control board tocontrol both the fluorometer and luminometer with a single controlboard.

The fluorometer can be used to perform dynamic dilution measurements forcytometry—this is currently done on the spectrometer, but thefluorometer would offer a more sensitive option. There is also thepotential option of doing additional functions of cytometry, thought notquite all the same capabilities as the cytometer.

Due to the high sensitivity of the electronics to EMI, the allelectronics need to be placed in a metal housing, which is grounded.Furthermore, the thickness of the housing's walls are designed such thatboth low (60 Hz) to high (kHz to MHz) frequencies are blocked.

System

In embodiments, devices comprising a femtowatt sensitivity photodiodeassembly, and systems and methods comprising or using such devices, maycomprise a controller. In embodiments, a controller may comprise aprocessor. In embodiments, a controller may be connected to, and maycontrol the operation of, components of a device; such components aretypically disposed within a housing of the device. In embodiments, acontroller may control the operation of a femtowatt sensitivityphotodiode assembly. In embodiments, a controller may control theoperation of a sample handling system. In embodiments, a controller maycontrol the operation of a detector. In embodiments, a controller maycontrol the operation of any component or unit of the device. Othercomponents may include, for example, a camera, a chemistry assay unit, anucleic acid assay unit, a heating unit, a communication unit, a proteinchemistry unit, or other component or unit. In embodiments, a controllermay control the operation of one or more components of a deviceaccording to a protocol. In embodiments, a protocol by which acontroller controls the operation of any one or more component or unitof a device may be preprogrammed, e.g., may be resident on the device.In embodiments, a protocol by which a controller controls the operationof any one or more component or unit of a device may be obtained fromanother device, or from a user, or from a laboratory, or from a network,or from the cloud. In embodiments, a protocol by which a controllercontrols the operation of any one or more component or unit of a devicemay be updated, or may be updatable, according to information orinstructions from another device, or from a user, or from a laboratory,or from a network, or from the cloud. In embodiments, a device mayreceive information, or instructions, or updates, or protocols, via auser interface. In embodiments, a device may receive information, orinstructions, or updates, or protocols, via a communication assembly.The system can, in one embodiment, have optical detectors at four levelsof sensitivity with the least sensitive is the spectrometer. Next iscytometer. Nucleic acid is more sensitive than cytometer. Then the PMTis most sensitive (3 to 4 orders of magnitude of sensitivity higher thanthe next most sensitive sensor).

In embodiments, devices comprising a femtowatt sensitivity photodiodeassembly, and systems and methods comprising or using such devices, maycomprise a display effective to provide a user with informationregarding the operation of the device, information regarding theprogress of an assay performed by the device, or information regardingthe results of an assay performed by the device. In embodiments, adisplay may comprise a visual display, or may comprise a printeddisplay, or may comprise an audio signal, which may include an audiosignal understandable as speech by a user, or may comprise anycombination or all of such displays. In embodiments, a display maycomprise a user interface. In embodiments in which a display comprises auser interface, a device may receive, e.g., information, commands,protocols, or other input.

In embodiments, devices comprising a femtowatt sensitivity photodiodeassembly, and systems and methods comprising or using such devices, maycomprise a communication assembly effective to communicate with one ormore of a user, another device, a laboratory, a network, the cloud, orother communication target. In embodiments, a communication assembly mayprovide a communication target with information regarding the operationof the device, information regarding the progress of an assay performedby the device, or information regarding the results of an assayperformed by the device. In embodiments, a communication assembly may beconfigured to allow a device to receive, e.g., information, commands,protocols, or other input from an outside source, such as, e.g., a user,another device, a laboratory, a network, the cloud, or othercommunication source.

As used herein the terms “sample handling system”, “fluid handlingsystem” and grammatical equivalents refer to systems configured toobtain, transport, and deliver fluids. In embodiments disclosed herein,such systems comprise pipettes, nozzles, pipette tips, mechanicalcomponents configured to move a pipette, a nozzle, or a pipette tip to adesired location. Such a desired location is typically within a housingof a device. In embodiments, a pipette tip may be mounted on a nozzle;in embodiments, a pipette tip may be removably mounted on a nozzle,effective that a nozzle may engage and mount a first pipette tip, usethe first pipette tip, discard the first pipette tip, and then engageand mount a second pipette tip. Such systems comprise means foraspirating liquid into a pipette tip. Such systems comprise means fordispensing liquid from a pipette tip. In embodiments of such systems, apipette and nozzle may engage and mount an element other than a pipettetip; for example, in embodiments disclosed herein, a pipette and nozzlemay engage and mate with a mating socket of a vessel (see, e.g., FIGS.10 and 11). In embodiments, a pipette and nozzle mated with a matingsocket of a vessel may be used to transport the vessel to a desiredlocation within a device. In embodiments, a pipette and nozzle matedwith a mating socket of a vessel may be used to apply force to a vessel(see, e.g., FIG. 11 for a configuration where such application of forcemay be useful).

The methods disclosed herein can be readily incorporated into and usedin device for processing a sample, or a system for processing a sample,which may be an automated assay device, or may be an automated assaysystem. Such assay devices and assay systems may comprise devices andsystems disclosed, for example, in U.S. Pat. Nos. 8,088,593; 8,380,541;U.S. patent application Ser. No. 13/769,798, filed Feb. 18, 2013; U.S.patent application Ser. No. 13/769,779, filed Feb. 18, 2013; U.S. patentapplication Ser. No. 13/244,947 filed Sep. 26, 2011; PCT/US2012/57155,filed Sep. 25, 2012; U.S. application Ser. No. 13/244,946, filed Sep.26, 2011; U.S. patent application Ser. No. 13/244,949, filed Sep. 26,2011; and U.S. Application Ser. No. 61/673,245, filed Sep. 26, 2011, thedisclosures of which patents and patent applications are all herebyincorporated by reference in their entireties.

Such a device, and such a system, may be useful for the practice of themethods disclosed herein. For example, a device may be useful forreceiving a sample. A device may be useful for preparing, or forprocessing a sample. A device may be useful for performing an assay on asample. A device may be useful for obtaining data from a sample. Adevice may be useful for transmitting data obtained from a sample. Adevice may be useful for disposing of a sample following processing orassaying of a sample.

A device may be part of a system, a component of which may be a sampleprocessing device. A device may be a sample processing device. A sampleprocessing device may be configured to facilitate collection of asample, prepare a sample for a clinical test, or effect a chemicalreaction with one or more reagents or other chemical or physicalprocessing, as disclosed herein. A sample processing device may beconfigured to obtain data from a sample. A sample processing device maybe configured to transmit data obtained from a sample. A sampleprocessing device may be configured to analyze data from a sample. Asample processing device may be configured to communicate with anotherdevice, or a laboratory, or an individual affiliated with a laboratory,to analyze data obtained from a sample.

A sample processing device may be configured to be placed in or on asubject. A sample processing device may be configured to accept a samplefrom a subject, either directly or indirectly. A sample may be, forexample, a biological sample, e.g., of blood, urine, sputum, materialobtained from a nasal swab, a throat swab, a cheek swab, or othersample, (e.g., a sample obtained from a fingerstick, or fromvenipuncture, or an arterial biological sample, e.g., of blood, urine,sputum, material obtained from a nasal swab, a throat swab, a cheekswab, or other sample,), a urine sample, a biopsy sample, a tissueslice, stool sample, or other biological sample; a water sample, a soilsample, a food sample, an air sample; or other sample. A biologicalsample, e.g., of blood, urine, sputum, material obtained from a nasalswab, a throat swab, a cheek swab, or other sample, may comprise, e.g.,whole blood, plasma, or serum. A sample processing device may receive asample from the subject through a housing of the device. The samplecollection may occur at a sample collection site, or elsewhere. Thesample may be provided to the device at a sample collection site.

In some embodiments, a sample processing device may be configured toaccept or hold a cartridge. In some embodiments, a sample processingdevice may comprise a cartridge. The cartridge may be removable from thesample processing device. In some embodiments, a sample may be providedto the cartridge of the sample processing device. Alternatively, asample may be provided to another portion of a sample processing device.The cartridge and/or device may comprise a sample collection unit thatmay be configured to accept a sample.

A cartridge may include a sample, and may include reagents for use inprocessing or testing a sample, disposables for use in processing ortesting a sample, or other materials. Following placement of a cartridgeon, or insertion of a cartridge into, a sample processing device, one ormore components of the cartridge may be brought into fluid communicationwith other components of the sample processing device. For example, if asample is collected at a cartridge, the sample may be transferred toother portions of the sample processing device. Similarly, if one ormore reagents are provided on a cartridge, the reagents may betransferred to other portions of the sample processing device, or othercomponents of the sample processing device may be brought to thereagents. In some embodiments, the reagents or components of a cartridgemay remain on-board the cartridge. In some embodiments, no fluidics areincluded that require tubing or that require maintenance (e.g., manualor automated maintenance).

A sample or reagent may be transferred to a device, such as a sampleprocessing device. A sample or reagent may be transferred within adevice. Such transfer of sample or reagent may be accomplished withoutproviding a continuous fluid pathway from cartridge to device. Suchtransfer of sample or reagent may be accomplished without providing acontinuous fluid pathway within a device. In embodiments, such transferof sample or reagent may be accomplished by a sample handling system(e.g., a pipette); for example, a sample, reagent, or aliquot thereofmay be aspirated into an open-tipped transfer component, such as apipette tip, which may be operably connected to a sample handling systemwhich transfers the tip, with the sample, reagent, or aliquot thereofcontained within the tip, to a location on or within the sampleprocessing device. The sample, reagent, or aliquot thereof can bedeposited at a location on or within the sample processing device.Sample and reagent, or multiple reagents, may be mixed using a samplehandling system in a similar manner. One or more components of thecartridge may be transferred in an automated fashion to other portionsof the sample processing device, and vice versa.

A device, such as a sample processing device, may have a fluid handlingsystem (also termed herein a sample handling system). A fluid handlingsystem may perform, or may aid in performing, transport, dilution,extraction, aliquotting, mixing, and other actions with a fluid, such asa sample. In some embodiments, a fluid handling system may be containedwithin a device housing. A fluid handling system may permit thecollection, delivery, processing and/or transport of a fluid,dissolution of dry reagents, mixing of liquid and/or dry reagents with aliquid, as well as collection, delivery, processing and/or transport ofnon-fluidic components, samples, or materials. The fluid may be asample, a reagent, diluent, wash, dye, or any other fluid that may beused by the device, and may include, but not limited to, homogenousfluids, different liquids, emulsions, suspensions, and other fluids. Afluid handling system, including without limitation a pipette, may alsobe used to transport vessels (with or without fluid contained therein)around the device. The fluid handling system may dispense or aspirate afluid. The sample may include one or more particulate or solid matterfloating within a fluid.

In embodiments, a fluid handling system may comprise a pipette, pipettetip, syringe, capillary, or other component. The fluid handling systemmay have portion with an interior surface and an exterior surface and anopen end. The fluid handling system may comprise a pipette, which mayinclude a pipette body and a pipette nozzle, and may comprise a pipettetip. A pipette tip may or may not be removable from a pipette nozzle. Inembodiments, a fluid handling system may use a pipette mated with apipette tip; a pipette tip may be disposable. A tip may form afluid-tight seal when mated with a pipette. A pipette tip may be usedonce, twice, or more times. In embodiments, a fluid handling system mayuse a pipette or similar device, with or without a pipette tip, toaspirate, dispense, mix, transport, or otherwise handle the fluid. Thefluid may be dispensed from the fluid handling system when desired. Thefluid may be contained within a pipette tip prior to being dispensed,e.g., from an orifice in the pipette tip. In embodiments, or instancesduring use, all of the fluid may be dispensed; in other embodiments, orinstances during use, a portion of the fluid within a tip may bedispensed. A pipette may selectively aspirate a fluid. The pipette mayaspirate a selected amount of fluid. The pipette may be capable ofactuating stirring mechanisms to mix the fluid within the tip or withina vessel. The pipette may incorporate tips or vessels creatingcontinuous flow loops for mixing, including of materials or reagentsthat are in non-liquid form. A pipette tip may also facilitate mixtureby metered delivery of multiple fluids simultaneously or in sequence,such as in 2-part substrate reactions.

A fluid handling system may include one or more fluidically isolated orhydraulically independent units. For example, the fluid handling systemmay include one, two, or more pipette tips. The pipette tips may beconfigured to accept and confine a fluid. The tips may be fluidicallyisolated from or hydraulically independent of one another. The fluidcontained within each tip may be fluidically isolated or hydraulicallyindependent from one fluids in other tips and from other fluids withinthe device. The fluidically isolated or hydraulically independent unitsmay be movable relative to other portions of the device and/or oneanother. The fluidically isolated or hydraulically independent units maybe individually movable. A fluid handling system may comprise one ormore base or support. A base or support may support one or more pipetteor pipette units. A base or support may connect one or more pipettes ofthe fluid handling system to one another.

A sample processing device may be configured to perform processing stepsor actions on a sample obtained from a subject. Sample processing mayinclude sample preparation, including, e.g., sample dilution, divisionof a sample into aliquots, extraction, contact with a reagent,filtration, separation, centrifugation, or other preparatory orprocessing action or step. A sample processing device may be configuredto perform one or more sample preparation action or step on the sample.Optionally, a sample may be prepared for a chemical reaction and/orphysical processing step. A sample preparation action or step mayinclude one or more of the following: centrifugation, separation,filtration, dilution, enriching, purification, precipitation,incubation, pipetting, transport, chromatography, cell lysis, cytometry,pulverization, grinding, activation, ultrasonication, micro columnprocessing, processing with magnetic beads, processing withnanoparticles, or other sample preparation action or steps. For example,sample preparation may include one or more step to separate blood intoserum and/or particulate fractions, or to separate any other sample intovarious components. Sample preparation may include one or more step todilute and/or concentrate a sample, such as a biological sample, e.g.,of blood, urine, sputum, material obtained from a nasal swab, a throatswab, a cheek swab, or other sample, or other biological samples. Samplepreparation may include adding an anti-coagulant or other ingredients toa sample. Sample preparation may also include purification of a sample.In embodiments, all sample processing, preparation, or assay actions orsteps are performed by a single device. In embodiments, all sampleprocessing, preparation, or assay actions or steps are performed withina housing of a single device. In embodiments, most sample processing,preparation, or assay actions or steps are performed by a single device,and may be performed within a housing of a single device. Inembodiments, many sample processing, preparation, or assay actions orsteps are performed by a single device, and may be performed within ahousing of a single device. In embodiments, sample processing,preparation, or assay actions or steps may be performed by more than onedevice.

A sample processing device may be configured to run one or more assay ona sample, and to obtain data from the sample. An assay may include oneor more physical or chemical treatments, and may include running one ormore chemical or physical reactions. A sample processing device may beconfigured to perform one, two or more assays on a small sample ofbodily fluid. One or more chemical reaction may take place on a samplehaving a volume, as described elsewhere herein. For example one or morechemical reaction may take place in a pill having less than femtolitervolumes. In an instance, the sample collection unit is configured toreceive a volume of the bodily fluid sample equivalent to a single dropor less of blood or interstitial fluid. In embodiments, the volume of asample may be a small volume, where a small volume may be a volume thatis less than about 1000 μL, or less than about 500 μL, or less thanabout 250 μL, or less than about 150 μL, or less than about 100 μL, orless than about 75 μL, or less than about 50 μL, or less than about 40μL, or less than about 20 μL, or less than about 10 μL, or other smallvolume. In embodiments, all sample assay actions or steps are performedon a single sample. In embodiments, all sample assay actions or stepsare performed by a single device. In embodiments, all sample assayactions or steps are performed within a housing of a single device. Inembodiments, most sample assay actions or steps are performed by asingle device, and may be performed within a housing of a single device.In embodiments, many sample assay actions or steps are performed by asingle device, and may be performed within a housing of a single device.In embodiments, sample processing, preparation, or assay actions orsteps may be performed by more than one device.

A sample processing device may be configured to perform a plurality ofassays on a sample. For example, a sample processing device may beconfigured to detect, or to identify, or to measure pathogen-identifyingmaterial in a sample. In embodiments, a sample processing device may beconfigured to perform a plurality of assays on a single sample. Inembodiments, a sample processing device may be configured to perform aplurality of assays on a single biological sample, where the biologicalsample is a small sample. For example, a small sample may have a samplevolume that is a small volume of less than about 1000 μL, or less thanabout 500 μL, or less than about 250 μL, or less than about 150 μL, orless than about 100 μL, or less than about 75 μL, or less than about 50μL, or less than about 40 μL, or less than about 20 μL, or less thanabout 10 μL, or other small volume. A sample processing device may becapable of performing multiplexed assays on a single sample. A pluralityof assays may be run simultaneously; may be run sequentially; or someassays may be run simultaneously while others are run sequentially. Oneor more control assays and/or calibrators (e.g., including aconfiguration with a control of a calibrator for the assay/tests) canalso be incorporated into the device; control assays and assay oncalibrators may be performed simultaneously with assays performed on asample, or may be performed before or after assays performed on asample, or any combination thereof. In embodiments, all sample assayactions or steps are performed by a single device. In embodiments, allof a plurality of assay actions or steps are performed within a housingof a single device. In embodiments, most sample assay actions or steps,of a plurality of assays, are performed by a single device, and may beperformed within a housing of a single device. In embodiments, manysample assay actions or steps, of a plurality of assays, are performedby a single device, and may be performed within a housing of a singledevice. In embodiments, sample processing, preparation, or assay actionsor steps may be performed by more than one device.

In embodiments, all of a plurality of assays may be performed in a shorttime period. In embodiments, such a short time period comprises lessthan about three hours, or less than about two hours, or less than aboutone hour, or less than about 40 minutes, or less than about 30 minutes,or less than about 25 minutes, or less than about 20 minutes, or lessthan about 15 minutes, or less than about 10 minutes, or less than about5 minutes, or less than about 4 minutes, or less than about 3 minutes,or less than about 2 minutes, or less than about 1 minute, or othershort time period.

A sample processing device may be configured to detect one or moresignals relating to the sample. A sample processing device may beconfigured to identify one or more properties of the sample. Forinstance, the sample processing device may be configured to detect thepresence or concentration of one analyte or a plurality of analytes or adisease condition in the sample (e.g., in or through a bodily fluid,secretion, tissue, or other sample). Alternatively, the sampleprocessing device may be configured to detect a signal or signals thatmay be analyzed to detect the presence or concentration of one or moreanalytes (which may be indicative of a disease condition) or a diseasecondition in the sample. The signals may be analyzed on board thedevice, or at another location. Running a clinical test may or may notinclude any analysis or comparison of data collected.

A chemical reaction or other processing step may be performed, with orwithout the sample. Examples of steps, tests, or assays that may beprepared or run by the device may include, but are not limited toimmunoassay, nucleic acid assay, receptor-based assay, cytometric assay,colorimetric assay, enzymatic assay, electrophoretic assay,electrochemical assay, spectroscopic assay, chromatographic assay,microscopic assay, topographic assay, calorimetric assay, turbidmetricassay, agglutination assay, radioisotope assay, viscometric assay,coagulation assay, clotting time assay, protein synthesis assay,histological assay, culture assay, osmolarity assay, and/or other typesof assays, centrifugation, separation, filtration, dilution, enriching,purification, precipitation, pulverization, incubation, pipetting,transport, cell lysis, or other sample preparation action or steps, orcombinations thereof. Steps, tests, or assays that may be prepared orrun by the device may include imaging, including microscopy, cytometry,and other techniques preparing or utilizing images. Steps, tests, orassays that may be prepared or run by the device may further include anassessment of histology, morphology, kinematics, dynamics, and/or stateof a sample, which may include such assessment for cells.

A device may be capable of performing all on-board steps (e.g., steps oractions performed by a single device) in a short amount of time. Adevice may be capable of performing all on-board steps on a singlesample in a short amount of time. For example, from sample collectionfrom a subject to transmitting data and/or to analysis may take about 3hours or less, 2 hours or less, 1 hour or less, 50 minutes or less, 45minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes orless, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4minutes or less, 3 minutes or less, 2 minutes or less, or 1 minute orless. The amount of time from accepting a sample within the device totransmitting data and/or to analysis from the device regarding such asample may depend on the type or number of steps, tests, or assaysperformed on the sample. The amount of time from accepting a samplewithin the device to transmitting data and/or to analysis from thedevice regarding such a sample may take about 3 hours or less, 2 hoursor less, 1 hour or less, 50 minutes or less, 45 minutes or less, 40minutes or less, 30 minutes or less, 20 minutes or less, 15 minutes orless, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3minutes or less, 2 minutes or less, or 1 minute or less.

A device may be configured to prepare a sample for disposal, or todispose of a sample, such as a biological sample, following processingor assaying of a sample.

In embodiments, a sample processing device may be configured to transmitdata obtained from a sample. In embodiments, a sample processing devicemay be configured to communicate over a network. A sample processingdevice may include a communication assembly that may interface with thenetwork. A sample processing device may be connected to the network viaa wired connection or wirelessly. The network may be a local areanetwork (LAN) or a wide area network (WAN) such as the Internet. In someembodiments, the network may be a personal area network. The network mayinclude the cloud. The sample processing device may be connected to thenetwork without requiring an intermediary device, or an intermediarydevice may be required to connect a sample processing device to anetwork. A sample processing device may communicate over a network withanother device, which may be any type of networked device, including butnot limited to a personal computer, server computer, or laptop computer;personal digital assistants (PDAs) such as a Windows CE device; phonessuch as cellular phones, smartphones (e.g., iPhone, Android, Blackberry,etc.), or location-aware portable phones (such as GPS); a roamingdevice, such as a network-connected roaming device; a wireless devicesuch as a wireless email device or other device capable of communicatingwireless with a computer network; or any other type of network devicethat may communicate possibly over a network and handle electronictransactions. Such communication may include providing data to a cloudcomputing infrastructure or any other type of data storageinfrastructure which may be accessed by other devices.

A sample processing device may provide data regarding a sample to, e.g.,a health care professional, a health care professional location, such asa laboratory, or an affiliate thereof. One or more of a laboratory,health care professional, or subject may have a network device able toreceive or access data provided by the sample processing device. Asample processing device may be configured to provide data regarding asample to a database. A sample processing device may be configured toprovide data regarding a sample to an electronic medical records system,to a laboratory information system, to a laboratory automation system,or other system or software. A sample processing device may provide datain the form of a report.

A laboratory, device, or other entity or software may perform analysison data regarding a sample in real-time. A software system may performchemical analysis and/or pathological analysis, or these could bedistributed amongst combinations of lab, clinical, and specialty orexpert personnel. Analysis may include qualitative and/or quantitativeevaluation of a sample. Data analysis may include a subsequentqualitative and/or quantitative evaluation of a sample. Optionally, areport may be generated based on raw data, pre-processed data, oranalyzed data. Such a report may be prepared so as to maintainconfidentiality of the data obtained from the sample, the identity andother information regarding the subject from whom a sample was obtained,analysis of the data, and other confidential information. The reportand/or the data may be transmitted to a health care professional. Dataobtained by a sample processing device, or analysis of such data, orreports, may be provided to a database, an electronic medical recordssystem, to a laboratory information system, to a laboratory automationsystem, or other system or software

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, with any of the above embodiments, it should be understoodthat different shaped reflectors can be used. Some may havecross-sectional shapes such as but not limited to elliptical,triangular, quadrilateral (e.g., square, rectangular, trapezoidal,parallelogram), pentagonal, hexagonal, heptagonal, octagonal, square,circular, star, other two dimensional patterns, or single or multiplecombinations of the foregoing. It should also be understood that thereflectors may be configured to be in certain three dimensionalconfigurations such as but not limited to tubular, cylindrical, disc,pyramid, mesa, or the like can also be adapted for use herein. Althoughthe examples herein are described in the context of photodiodes, itshould be understood that other solid-state or semiconductor (non-vacuumtube) detectors can also be adapted for use herein.

Additionally, concentrations, amounts, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited. Forexample, a size range of about 1 nm to about 200 nm should beinterpreted to include not only the explicitly recited limits of about 1nm and about 200 nm, but also to include individual sizes such as 2 nm,3 nm, 4 nm, and sub-ranges such as 10 nm to 50 nm, 20 nm to 100 nm, etc.. . . .

The publications discussed or cited herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.All publications mentioned herein are incorporated herein by referenceto disclose and describe the structures and/or methods in connectionwith which the publications are cited. The following applications arefully incorporated herein by reference for all purposes: U.S. Pat. Nos.8,088,593; 8,380,541; U.S. patent application Ser. No. 13/769,798, filedFeb. 18, 2013; U.S. patent application Ser. No. 13/769,779, filed Feb.18, 2013; U.S. Pat. App. Ser. No. 61/766,113 filed Feb. 18, 2013, U.S.patent application Ser. No. 13/244,947 filed Sep. 26, 2011;PCT/US2012/57155, filed Sep. 25, 2012; U.S. application Ser. No.13/244,946, filed Sep. 26, 2011; U.S. patent application Ser. No.13/244,949, filed Sep. 26, 2011; and U.S. Application Ser. No.61/673,245, filed Sep. 26, 2011, U.S. Patent Application Ser. No.61/786,351 filed Mar. 15, 2013, U.S. Patent Application Ser. No.61/697,797 filed Sep. 6, 2012, U.S. Patent Application Ser. No.61/801,996 filed Mar. 15, 2013, and U.S. Patent Application Ser. No.61/733,886 filed Dec. 5, 2012, the disclosures of which patents andpatent applications are all hereby incorporated by reference in theirentireties for all purposes.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. Any feature, whetherpreferred or not, may be combined with any other feature, whetherpreferred or not. The appended claims are not to be interpreted asincluding means-plus-function limitations, unless such a limitation isexplicitly recited in a given claim using the phrase “means for.” Itshould be understood that as used in the description herein andthroughout the claims that follow, the meaning of “a,” “an,” and “the”includes plural reference unless the context clearly dictates otherwise.For example, a reference to “an assay” may refer to a single assay ormultiple assays. Also, as used in the description herein and throughoutthe claims that follow, the meaning of “in” includes “in” and “on”unless the context clearly dictates otherwise. Finally, as used in thedescription herein and throughout the claims that follow, the meaning of“or” includes both the conjunctive and disjunctive unless the contextexpressly dictates otherwise. Thus, the term “or” includes “and/or”unless the context expressly dictates otherwise.

1-14. (canceled)
 15. A method comprising: detecting a signal atfemtowatt sensitivity by using a plurality of photodiodes to collectlight emitted from a sample to generate said signal and then amplifyingsaid signal by: using an analog amplification system comprising at leasta high gain transimpedance amplifier (TIA) and at least a buffer on eachof said photodiodes, followed by a fully differential amplifier tocombine outputs of multiple TIAs; and using a digital acquisition systemon said signal comprising at least one analog-to-digital converter(ADC), followed by a programmable processor to detect, which is linkedto a central processor as well as on-board memory, wherein theprogrammable processor implements a data acquisition algorithm, whereinthe programmable processor implements the data acquisition algorithmusing a long time average.
 16. The method of claim 15 further comprisingcontaining said analog amplification system in a mechanical housingmodule.
 17. The method of claim 15 wherein the sample comprises a bloodsample.
 18. The method of claim 15 further comprising using multipledigital-to-analog converters (DACs) on the programmable processorconfigured to provide feedback control
 19. The method of claim 18wherein one of said DACs is configured for offset adjustment in thedifferential amplifier, and one of said DACs is set the reference levelof the ADC.
 20. The method of claim 15 further comprising using at leastone shaped reflector to direct light to at least one of saidphotodetectors.
 21. The method of claim 20 wherein the shaped reflectorhas a semi-hemispherical shape.
 22. The method of claim 20 wherein theshaped reflector comprises at least one opening sized and positioned toallow a sample vessel to be placed at a desired location in a cavitydefined at least in part by the shaped reflector.